A COAGULATION FACTOR VIII FORMULATION

Abstract: The present invention relates to a pharmaceutical formulation for subcutaneous, intramuscular or intradermal administration comprising recombinant coagulation factor VIII and use thereof for manufacture of a medicament for treating haemophilia. The formulation comprises a highly purified recombinant coagulation factor VIII in a concentration of at least 1000 IU/ml, which gives surprisingly high levels of active factor VIII in the blood stream after subcutaneous, intramuscular or intradermal administration. The formulation is intended for treatment of haemophilia by subcutaneous, intramuscular or intradermal administration. The recombinant factor VIII is preferably a deletion derivative thereof, which can be used for the manufacture of a medicament for subcutaneous administration.

Description: A coagulation factor VIII formulation . The present invention relates to a pharmaceutical formulation for subcutaneous, intramuscular or intradermal administration com¬ prising recombinant coagulation factor vm and use thereof for manufacture of a medicament for treating haemophilia. The for¬ mulation comprises a highly purified recombinant coagulation factor VHI in a concentration of at least 1000 IU/ml, which gives surprisingly high levels of active factor VIE in the blood stream after subcutaneous, intramuscular or intradermal administration. The formulation is intended for treatment of haemophilia by sub¬ cutaneous, intramuscular or intradermal administration. The re¬ combinant factor VTA is preferably a deletion derivative thereof, which can be used for the manufacture of a medicament for sub¬ cutaneous administration. Background of the invention Haemophilia is an inherited disease which has been known for centuries but it is only within the last three decades that it has been possible to differentiate between the various forms; hae¬ mophilia A, haemophilia B and haemophilia C. Haemophilia A is the most frequent form. It affects only males with an incidence of one or two individuals per 10 000 live-born males. The disea¬ se is caused by strongly decreased level or absence of biological¬ ly active coagulation factor vm (antihaemophilic factor), which is a protein normally present in plasma. The clinical manifesta¬ tion of haemophilia A is a strong bleeding tendency and before treatment with factor vm concentrates was introduced, the mean age of those patients was less than 20 years. Concentrates of factor Vm obtained from plasma have been available for about three decades. This has improved the situation for treat¬ ment of haemophilia patients considerably and given them possi- bility to live a normal life. Therapeutic factor V_H concentrates have until now been prepa- red by fractionation of plasma. However, there are now methods available for production of factor Vm in cell culture using re¬ combinant DNA techniques as reported in e.g. J Gitschier et al. Nature 312, p. 330-37, 1984 and EP-A-160 457. Factor vm concentrates derived from human plasma contain several fragmented fully active factor VI forms (Andersson et al, Proc. Natl. Acad. Sci. USA, Vol 83, p. 2979-83, May 1986). The smallest active form has a molecular mass of 170 kDa and con- sists of two chains of 90 kDa and 80 kDa held together by a metal ion bridge. Reference is here made to EP-A-197 901. Kabi Pharmacia has developed a recombinant factor VHI product which corresponds to the 170 kDa plasma factor VHI form in therapeutic factor VIII concentrates. The truncated recombinant factor VU3 molecule is termed r-Vϋl SQ_and is produced by Chinese Hamster Ovary (CHO) cells in a cell culture process in serum-free medium. The structure and biochemistry of recombinant factor VIII prod- ucts in general have been described by Kaufman in Tibtech, Vol 9, 1991 and Hematology, 63, p. 155-65, 1991. The structure and bio¬ chemistry of r-vm SO_have been described in WO-A-91/09122. Large proteins are normally given intravenously so the medicament directly available in the blood stream. It would however be advanta¬ geous if a medicament could be given subcu taneously, intramuscula or intradermally as these administration forms are much easier to handle for the patient. Especially if the medicament must be taken regularly during the whole life and treatment is to start early, alrea when the patient is a child. However, a medicament with a very large and labile molecule, such as coagulations factor VQI of 170 to 300 kDa, have normally a very low bioaviability if given subcutaneously, intramuscularly or intrade mally, since the uptake is not enough and degradation is severe. To our knowledge, the only coagulation factor protein which has been administered by subcutaneous injection is factor DC (90 kDa). All presently avialable factor VIII preparations on the market are made as a formulation for intravenous administration and are stabil sed with human serum albumin. Description of the invention To our great surprise we have found that factor Vπi, which is a very sensitive protein, can be given subcutaneously and, in contrast to al earlier experience we obtain an acceptable absorption and a high le of active factor VHI protein in the blood. We have thus developed a formulation which makes it possible to administer factor VHI subcutaneously, intramuscularly or intrader- mally and which gives a great advantage for all patients in need of factor Vm. Recombinant factor m SO_is indicated for treatment of classical haemophilia. The half-life for r-VDI SO_is approximately 12 hours for humans when injected intravenously. For prophylactic treatment 15-25 IU/kg bodyweigt is given of factor Vm three times a week. An intravenous injection is normally 5-10 ml. An injection given subcutaneously is between 0.05 to 1 ml and the concentration of factor V must therefore be very high in such a formulation. This is possible to obtain e.g. with our highly purified recombinant factor Vm. The inventive idea is thus a combination of the finding that factor v can be absorbed into the blood-stream when given as a subcuta¬ neous, intramuscular or intradermal pharmaceutical formulation an that it is possible to produce a formulation comprising the required high concentration of factor vm for this purpose. The present invention relates to a pharmaceutical formulation for subcutaneous, intramuscular or intradermal aclininistration comprising highly purified recombinant coagulation factor VIII in a concentration of at least 1000 IU/ml, which formulation gives a therapeutic level of factor Vm activity in the blood after aclministration. The composition is preferably given subcutaneously. The factor VIII activity in the formulation is at least 1000 IU/ml, preferably more than 1500 IU/ml and most preferably from 5000 to 100 000 IU/ml. The volume given is suitably 0.1 to 2 ml, preferably 0.25 to 1.5 ml, and more preferably 0.5 to 1 ml. The volume can also be 0.1 to 1 ml. Factor Vm is recombinant and it can be either in its full-length form or preferably a deletion derivative thereof. More preferably the deletion derivative is recombinant factor Vm SO_(r-Vm SQ). By deletion derivative is here meant coagulation factor Vffl, in which the whole or part of the B-domain is missing. Additionally, the r-Vm SO_molecule can be chemically modified, e.g. by pegy- lation, covalentiy linked carbohydrates or polypeptides, in order to improve the stability of the molecule in vivo. Our used factor VTfl is highly purified, i.e. has a specific activity of more than 5000 IU/mg protein, even more than 12 000 IU/mg and is preferably stabilized without the addition of albumin. The formulation can also comprise sodium or potassium chloride, preferably in an amount of more than 0.1 M. Calcium (or other divalent metal ions) is necessary for the main¬ tenance of the association of factor Vm heavy and light chain. It is here added as calcium chloride (CaCl2) but other salts such as calcium ghiconate, calcium glubionate or calcium glucep tate can also be used. The composition comprises preferably calcium chlo- ride or calcium gluconate in an amount of more than 0.5 mM. An amino acid is preferably used to buffer the system and it also protects the protein in the amorphous phase if the formulation is freeze-dried. A suitable buffer could be L-histidine, lysine and/or arginine. L-Histidine has primarily been chosen because of the good buffer capacity of L-histidine around pH 7. The formulation could comprise i) at least 1500 IU/ml of a deletion derivative of recombinant factor Vm ii) at least 0.01 mg/ml of a polyoxyethylene sorbitan fatty acid ester iii) sodium chloride, preferably in an amount of more than 0.1 M. iv) calcium salt, such as calcium chloride or calcium gluconate, preferably in an amount of more than 0.5 mM. v) an amino acid such as L-histidine in an amount of more than 1 mM. A non-ionic surfactant can also be present in the formulation and is then preferably chosen from block co-polymers, such as a polo- xamer or polyoxyethylene sorbitan fatty acid ester, such as poly- oxyethylene-( 20) -sorbitan monolaurate or polyoxyethylene-(20)- sorbitan monooleate. The non-ionic surfactant, if used, should preferably be present in an amount above the critical micelle concentration (CMC). See Wan and Lee, Journal of Pharm Sci, 63, p. 136, 1974. The polyoxyethylene sorbitan fatty acid ester is preferably used in an amount of at least 0.01 mg/ml. To this formulation mono- or disaccharides or sugar alcohols, preferably sucrose, could be added. Also antioxidants such as gluthatione, acetylcystein, tocopherol, methionin, EDTA, citric acid, butyl hydroxy toluene and/or butyl hydroxy anisole could be added. Furthermore, preservatives such as benzyl alcohol, phenol, sorbic acid, parabens and chlorocresol could be added. The formulation comprises preferably L-histidine and sucrose. The ratio of sodium chloride to L-histidine and sucrose in the composition for freeze-drying is suitably more than 1:1 (w * .w), preferably more than 2:1 (w:w). The formulation could be in a dried form, preferably freeze- dried. The dried product is reconstituted with sterile water for injection or a pharmaceutically acceptable buffer solution, or mixed or reconstituted with an aqueous solution containing ab¬ sorption enhancers or protease inhibitors before administration. The claimed formulation can also be a stable aqueous solution ready for aclministration. It can also be a dispersion, e.g. a sus¬ pension, a liposomal formulation or an emulsion. The formulation could be stored in an oxygen-reduced environ- ment as disclosed in the copending patent application PCT7- SE94/00265. Absorption enhancers or protease inhibitors could be added. Examples of suitable absorption enhancers are phospholipids, fatty acids, bile salts, salicylates and EDTA. Examples of suitable protease inhibitors are aprotinin and EDTA. The claimed formulation can be prepared by mixing factor Vm with a non-ionic surfactant in an aqueous solution, preferably together with an amino acid such as L-histidine, sodium salt, suc¬ rose and a calcium salt or by eluating factor Vm from the last purification step with a buffer containing a non-ionic surfactant in an aqueous solution, preferably together with sodium salt, sucrose, calcium salt and an amino acid such as L-histidine. The invention also relates to the use of the claimed formulation for the manufacture of a medicament for subcutaneous, intra¬ muscular or intradermal administration for treating haemophilia, preferably for the use of a deletion derivative of recombinant factor vm for the manufacture of a medicament for subcutane¬ ous aclministration. The medicament can be in a stable aqueous solution or dispersion, or freeze-dried. It also relates to a method for treatment of haemophilia by subcutaneous, intramuscular or intradermal aclministration of the claimed formulation. The data presented in the examples indicate that r-\TII SO_can be injected subcutaneously and recovered in an active form in¬ travenously in vivo. This is a very surprising finding, as no such formulation have been known earlier. The protection is not limited to a composition under these examp- les. EXPERIMENTAL Material and methods The production of recombinant factor \TII SO_ (r-VIII SQ) was essentially performed as described in patent WO-A-91/O9122, example 1-3. A DHFR deficient CHO celline (DG44N.Y.) was elec- troporated with an expression vector containing the r-vm SQ. gene and an expression vector containing the dihydroflolate- reductase gene. Following selection on selective media surviving colonies were amplified through growth in stepwise increasing amounts of methotrexate. Supernatant from the resulting colo¬ nies were individually screened for factor Vm activity. A produ¬ ction clone was chosen and this was subsequently adapted to serum free suspension growth in a defined medium and finally a large scale fermentation process was developed. Supernantant is collected after certain time periods and further purified as desc¬ ribed below. The clarified conditioned medium was pH adjusted and applied to a S-Sepharose FF column. After washing, factor vm was eluated with a salt buffer containing 5 mM CaCl2. Immunoadsorption was carried out on an i_mmunoaffinity resin wher the ligand was a monoclonal antibody (8A4) directed towards the heavy chain of factor Vm. Before loading to the column the S-eluate was treated with 0.3 % TNBP and 1 % Octoxynol 9. The column was equilibrated, washed and factor VIII was eluated with a buffer containing 0.05 M CaCl2 and 50 % ethylene glycol. The mAb-eluate was loaded on a 0_-Sepharose FF column, equilibrate with the elution buffer in the immimoaffinity step. After washing, factor Vm was eluated with 0.05 M L-Histidine, 0.6 M sodium chlo¬ ride, 4 mM calcium chloride and pH 6.8. The Q.-eluate was applied to a gel filtration column (Superdex 200 p.g.). Equilibration and elution was carried out with a buffer contai¬ ning L-histidine, sodium chloride and calcium chloride. The protein peak was collected and the solution was formulated before freeze-drying. This material of r-Vffl SO_ was received from the final purifica¬ tion step. The factor Vm activity and the concentration of the inactive components were adjusted by diluting with an appro¬ priate buffer containing polyethylene glycol (PEG). The solution was then sterile filtered (0.22 μm), dispensed and freeze-dried. EXAMPLE 1 Recombinant factor vm was prepared according to the method described under Experimental. The freeze-dried composition containing r-VUI SO_was the following per vial, which was reconstituted in 4 ml sterile water for injection: Composition per vial: L-Histidine, mg 31.0 Sodium chloride, mg 70.1 Calcium chloride • (2 H2O), mg 2.35 Polyethylene glycol (PEG 4000), mg 4.0 Polyoxyethylene-( 20)-sorbitan monooleate (Tween 80®), mg 1 vm:C charged, IU/vial 4400 Vm:C in reconstituted solution, IU/ml 1060 Male albino mice weighing about 30 g and of strain NMRI, SPF, were injected subcutaneously in the neck with the reconstituted r-Vm SQ. solution. The volume injected at the dose level of 10 000 IU/kg was 9.4 ml/kg and at the higher dose level 50 000 IU/kg, 5 times larger, 47 ml/kg. In the placebo treatment saline was used, 9.4 ml/kg. 3-5 minutes before the blood sampling the mice were anaestheti¬ zed intra peritoneally with Mebumal® (pentobarbital) vet. 60 mg/ml. The volume injected was 9.4 ml/kg i.e. about 0.3 ml/- mouse. Under the anaesthesia 0.45 ml blood was collected from the vena cava in plastic syringes containing 0.05 ml 0.13 M sodium citrate. Plasma was then prepared from the collected blood by centrifugation (8800 g for 7 minutes) and kept frozen in plastic Cryoflex tubes at -70°C until the time of determination of factor VM activity. Results; TABLE 1 Vm:C in plasma from mice receiving r-Vm SQ.10 000 IU/kg body weight subcutaneously. Time after vm:c n administration (IU / ml) number of ( hours ) X ± Sd observations 0 0.82 ± 0.43 12 O.33 1.23 ± 0.41 3 1.0 1.38 ± 0.56 4 1.5 1.83 ± O.6O 12 2.0 1.43 ± 0.91 8 4.0 1.34 ± 0.72 6 6.0 1.27 ± 0.42 4 8.0 1.55 ± 0.80 4 16.0 0.62 ± 0.28 4 20.0 0.58 ± 0.12 3 24.0 0.76 ± 0.53 4 TABLE 2. Dose - Response in mice receiving r-Viπ SQ_subcutaneosly. Dose: Dose r-Viπ SCI administrated (IU/kg). Response: vm:C in plasma (IU/ml) 1.5 hours after subcutaneous administration. Dose Response Response n (IU/kg) (IU/ml) (IU/ml) number of obs (baseline adjusted) Blank 0.82 ± 0.43 - 12 (baseline) Saline 1.21 ± 0.34 0.39 4 10 000 1.83 ± 0.60 1.01 12 50 000 2.47 ± 0.60 1.65 6 Results 1. The change of VTfl:C in plasma with time after a subcutaneous dose of r-Vm SQ, 10 000 IU/kg, shows the typical pattern for a drug beeing absorbed from a subcutaneous depot (see Table 1). The maximum VϋI:C level in plasma is seen at about 1.5 hours after administration (see Table 1). 2. The absorption of r-Vm SQ.from a subcutaneous depot is fur¬ ther verified by the increase in maximum concentration seen when the dose is increased five-fold. No significant effect was observed on the obtained plasma level of Vffi:C when the subcu¬ taneous injection volume was changed from 9.4 to 47 ml/kg while the dose of r-Vm SQ,was kept constant. Furthermore, the Vm:C obtained in plasma was essentially not dependent on the osmolality of the administration solution. 3. The bioavailability of r-Vm SQ. after subcutaneous administra¬ tion in mouse was about 10% of the bioavailability after intrave- nous administration. The bioavailability was calculated from the area under the activity (V_H:C) - time curve. EXAMPLE 2. Plasma derived factor VM was used. The composition of the frozen solution containing plasma derived factor Vm was the following: Composition per ml: L-Histidine, mg 7.8 Sodium chloride, mg 35.1 Calcium chloride • (2 H2O), mg 0.59 Polyethyleneglycol (PEG 4000), mg 1.0 Albumin human, mg 10.0 Male albino mice weighing about 30 g and of strain NMRI, SPF, were injected subcutaneously in the neck with the reconstituted factor Vm solution. The volume injected at the dose level of 10 000 IU/kg was about 40 ml/kg. In the placebo treatment a solution containing 9% (w/v) sodium chloride was used. 3-5 minutes before the blood sampling the mice were anaesthetized intra peritoneally with Mebumal® (pentobarbital) vet. 60 mg/ml. The dose volume was about 1.2 ml/mouse. Under anasthesia 0.45 ml blood was collect¬ ed from vena cava in plastic syringes containing 0.05 ml sodium citrate (0.13 M). Plasma was prepared from the blood by centri¬ fugation (8800 g for 7 minutes) and thereafter stored in plastic Cryoflex tubes at -70 °C until determination of VM:C. Results: TABLE 3 VIILC in plasma from mice receiving plasma derived factor VIII, 10 000 IU/kg, subcutaneously. VIILC in the administration solu¬ tion was about 250 IU/ml. Time after VIILC (IU/ml) n administration X±SD number of observations (hours) 0 1.04±0.30 4 1 1.20±0.53 4 1.5 1.39±0.04 4 2 O.85±0.34 4 4 1.19±0.49 4 6 1.32±0.53 4 8 1.15±0.39 4 16 1.27±0.08 4 20 1.17±0.41 4 24 1.32±0.21 4 Results: 1. The bioavailabi ty of plasma derived factor V is fairly low accor ing to the results of the in vivo study in mice (Table 3). The bioavail hty of plasma derived factor m is roughly about 1/10 of the bioava labihty of r-Vm SQ, Hence, the bioavailabihty of r-Vffl SO_is substan¬ tially higher than the bioavailabihty of factor vm derived from hum plasma. The maximum plasma level of VHI:C is seen about 1.5 hours after subcutaneous administration. EXAMPLE 3 Recombinant factor vm was prepared according to the method described under Experimental with the following exceptions: (i) the material of r-VIII SO_that was received from the final purification step was diluted with a buffer not containing PEG, (ii) the r-VIII SQ. solution was not freeze-dried, it was stored at -70°C. The r-VIII SQ_-solution had the following composition: Composition per vial: L-Histidine, mg 7.5 Sucrose, mg 158 Sodium chloride, mg 45 Calcium chloride • (2 H2θ), mg 1.25 Polyoxyethylene-( 20) -sorbitan monooleate (Tween 80®, mg) 0.50 Vm:C charged, IU/vial 6070 VIII:C, IU/ml * 1130 * Diluted r-VIII SQ.-solution ( 1 part of r-Vm SQ.-solution +1 part of water, vrv) The r-VIII SQrSolution was diluted with sterile water for injection ( 1 part of r-VIII SO_-solution + 1 part of water, v:v) prior to admini- stration when the dose of vm:C was below 3000 IU/kg body- weight. Female cynomolgus monkey (Macaca fascicularis) weighing about 3-3.5 kg were injected with the r-VIII SQ.-solution subcutaneously in the dorsal region. Depending on the dose, the volume of injec¬ tion was varied between approximately 0.2 to 2.0 ml/kg body- weight. Subcutaneous injections with single doses of 250, 2500 and 5000 IU/kg were administered. On each sampling occasion 1.8 ml of blood was collected into tubes containing citrate as anticoa- gulant (0.2 ml). After centrifugation plasma was separated and frozen in aliquots (< -60°C). Results: TABLE 4 Vm:C in plasma from monkeys receiving r-VIII SQ, 250 IU/kg, subcutaneously. The VQI:C in the administration solution was about 1130 IU/ml. Monkey No 1 Sampling VIILC VΠLC VIILC after inj. (IU/ml) (IU/ml) (IU/ml) (Hours) 0 2.15 1.49 1.76 11 22..3322 1.75 1.92 4 2.43 1.52 1.89 8 2.48 1.67 1.92 10 2.41 1.76 2.03 12 2.29 1.70 2.01 1144 22..2200 1.69 2.00 24 1.76 1.32 1.98 30 2.31 1.46 1.90 48 2.18 1.64 1.96 TABLE 5 VIILC in plasma from monkeys receiving r-VM SQ, 2500 IU/kg, subcutaneously. The VIILC in the administration solution was about 1130 IU/ml. Monkey No 4 5 6 Sampling VIILC VIILC VIILC after inj. (IU/ml) (IU/ml) (IU/ml) (Hours) 0 1.95 1.35 2.30 2 2.43 1.86 3.05 6 3.51 2.45 3.59 9 3.91 2.47 4.16 11 3.47 2.24 3.68 13 3.11 2.06 3.34 22 2.38 1.55 2.79 40 2.01 1.49 2.38 TABLE 6 VIILC in plasma from monkeys receiving r-VIII SQ, 5000 IU/kg, subcutaneously. The VIILC in the administration solution was about 2470 IU/ml. Monkey No 7 8 Sampling VIILC vm:c vm:c after inj. (IU/ml) (IU/ml) (IU/ml) (Hours) 0 2.04 1.78 1.54 2 2.99 2.37 2.99 6 4.56 3.33 5.32 9 4.75 3.89 5.70 11 4.72 3.82 5.46 13 4.23 3.06 4.63 22 3.03 2.33 3.46 40 2.76 1.77 2.60 TABLE 7 Dose - Response in monkey receiving r-VM SQ. subcutaneously. Dose: Dose r-Viπ SQ. administrated (IU/kg bodyweight). Response: VIILC in plasma (IU/ml) about 9 hours after admini¬ stration. Dose Response Response n (IU/kg) (IU/ml) (IU/ml, number of baseline adj.) observations Blank 1.8 ± 0.3 (baseline) 250 0.37 ± 0.05 3 2500 1.70 ± 0.06 3 2500 2.05 ± 0.57 3 5000 3.4 ± 1.20 3 es lts 1. According to the results (table 4-6) the plasma concentration as a function of time follows the typical pattern for a drug being absorbe after subcutaneous aclministration. The maximum concentration of VHLC is seen about 9 hours after administration. 2. The dose-response relationship obtained (table 7), gives a further verification that there is an absorption of VIILC into the blood stream following a subcutaneous injection. 3. The bioavailabihty of r-VQI SQ. after subcutaneous administration i monkey was about 5-10 %. The bioavailabihty was calculated from th area under the activity (VIILC) - time curve. The bioavailabihty was essentially independent of the dose of r-VIII SQ,

Claims: CLAIMS 1. A pharmaceutical formulation for subcutaneous, intramuscular or intradermal administration comprising highly purified recom¬ binant coagulation factor \TH in a concentration of at least 1000 IU/ml, which formulation gives a therapeutic level of factor VIII activity in the blood after administration. 2. A formulation according to claim 1 which is adopted for sub¬ cutaneous administration. 3. A formulation according to any of claims 1 to 2 in which the factor Vm activity is more than 1500 IU/ml, preferably from 5000 to 100000 IU/ml. 4. A formulation according to any of claims 1 to 3 which has a volume of 0.1 to 2 ml, preferably 0.5 to 1 ml. 5. A formulation according to any of claims 1 to 4 in which factor Vm has been chemically modified. 6. A formulation according to any of claims 1 to 5 in which factor Vm is a deletion derivative of recombinant coagulation factor vm. 7. A formulation according to claim 1, comprising i) at least 1500 IU/ml of a deletion derivative of recombinant factor Vm ii) at least 0.01 mg/ml of a polyoxyethylene sorbitan fatty acid ester hi) sodium chloride, preferably in an amount of more than 0.1 M. iv) calcium salt, such as calcium chloride or calcium gluconate, preferably in an amount of more than 0.5 mM. v) an amino acid, such as L-histidine, in an amount of more than I mM. 8. A formulation according to claims 6 or 7 in which the deletion derivative factor VIII is deletion derivative recombinant factor 9. A formulation according to any of claims 1 to 8 which is a stable aqueous solution ready for administration. 10. A formulation according to any of claims 1 to 8 which is freeze-dried and reconstituted with sterile water or a pharma- ceutically acceptable buffer solution before administration. 11. A formulation according to any of claims 1 to 8 which is mixed or reconstituted with an aqueous solution containing ab¬ sorption enhancers or protease inhibitors before administration. 12. Use of a formulation according to any of claims 1-11 for the manufacture of a medicament for subcutaneous, intramuscular or intradermal administration for treating haemophilia. 13. Use of a deletion derivative of recombinant factor VIII for the manufacture of a medicament for subcutaneous administra¬ tion. 14. Use of a formulation or deletion derivative according to claims 12 or 13, where the medicament is in a stable aqueous solution or dispersion, or is freeze-dried. 15. Method for treatment of haemophilia by subcutaneous, intra¬ muscular or intradermal aάlministration of a formulation accord- ing to any of claims 1-11.

Inventors: OESTERBERG THOMAS, SPIRA JACK, WIDLUND LARS, OESTERBERG, THOMAS, SPIRA, JACK, WIDLUND, LARS
Applicants: OESTERBERG THOMAS, PHARMACIA AB, SPIRA JACK, WIDLUND LARS, OESTERBERG, THOMAS, SPIRA, JACK, WIDLUND, LARS
Application year: 1994
Main classification: A61K37
IPC codes: A61K38, A61P7